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Retinoblastoma (RB) is a primary intraocular malignancy in childhood, and may develop relapse and metastatic disease. This study was to identify the stem-cell properties of primary retinoblastoma cells critical to tumorigenesis and metastasis. Primary cells were isolated from fresh human RB tissues after enucleation, and cultured in serum-free or serum-enriched conditions, with two RB cell-lines Weri-RB1 and Y79 for comparison. Proliferation of primary RB cells were well-maintained in serum-free condition of DMEM/F12 medium, and formed stem-cell like spheroids. The immaturity of cultured primary RB cells was demonstrated by tendency of highly expressed stem-cell markers (CD133, Nestin and OCT4) and suppressed mature retinal-cell markers (GFAP, MAP2 and Recoverin). CD133, a neural stem-cell marker being exclusively studied in RB, was found positive in small patches of cells in archival human RB by immunohistochemistry. Meanwhile, at initial isolation, insignificant CD133+ cells were detected by flow-cytometry, and substantial increase of positivity was observed after several days cultivated in serum-free condition. Cultured primary RB cells were engrafted in subretinal region of BALB/c nude mice for assessment of tumorigenicity. Strong tumorigenic activity and extensive progression of the xenograft retinoblastoma was induced by primary cells as compared with the two cell-lines. Again, immunohistochemistry confirmed that the stem-cell markers were emphasized in the xenograft tumor in mice. Our findings demonstrated that in comparison to the well-established RB cell-lines, cultured primary RB cells possess stem-cell like properties with highly expressed stem-cell markers, self-regenerative growth in culture, and strong in vivo oncogenic potentiality.
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Células Madre Neoplásicas/patología , Células-Madre Neurales/patología , Neoplasias de la Retina/patología , Retinoblastoma/patología , Antígeno AC133/metabolismo , Animales , Biomarcadores/metabolismo , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Niño , Modelos Animales de Enfermedad , Xenoinjertos , Humanos , Inmunohistoquímica/métodos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células Madre Neoplásicas/metabolismo , Células-Madre Neurales/metabolismo , Fenotipo , Neoplasias de la Retina/metabolismo , Retinoblastoma/metabolismoRESUMEN
PURPOSE: To investigate whether inactive thyroid-associated ophthalmopathy (TAO) affects retinal oxygen saturation and/or vessel diameter. METHODS: Via an observational case-control study, retinal circulation was measured in patients with inactive TAO (mild, moderate, and severe) and normal subjects by retinal oximetry. Complete ophthalmologic examination, including noncontact tonometry and Hertel exophthalmometry, was performed; history of smoking and dysthyroid disease were recorded. Analysis of variance or the Kruskal-Wallis test was used to compare oximetry values between TAO and controls. Simple linear regression was used to analyze the correlation of Hertel, smoking, and intraocular pressure with oximetry values. RESULTS: Seventy-six eyes were enrolled: 19 controls, and 17 mild, 21 moderate, and 19 severe inactive TAO. Retinal oxygen saturation did not change significantly in inactive TAO versus controls; arteriole saturation: severe, 95.7% ± 7.0%; moderate, 93.2% ± 3.9%; mild, 90.3% ± 4.8%; and controls, 93.1% ± 6.4%; vein saturation: severe, 57.4% ± 7.1%; moderate, 59.0% ± 7.0,; mild, 56.3% ± 7.9%; and controls, 58.5% ± 6.5%; arteriovenous saturation: severe, 38.3% ± 8.0%; moderate, 34.2% ± 7.1%; mild, 33.9% ± 6.8%; and controls, 34.6% ± 5.9%. However, retinal venous diameter with severe TAO (137.3 ± 12.5 µm) significantly decreased in comparison with controls (148.8 ± 10.2 µm, p = 0.017). Otherwise, no significant change in vessel diameter was found between TAO and controls. No statistically significant correlations were found between Hertel values or intraocular pressure and oximetry values. However, there was a positive significant correlation between smoking and arteriovenous oxygen saturation (p = 0.017, ß = 4.61). CONCLUSIONS: In inactive TAO versus controls, retinal oxygen saturation fluctuated and could be affected by smoking; however, the retinal venous diameter only decreased significantly for severe TAO. This implies that TAO may affect retinal circulation; this effect could be accelerated by smoking.
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Oftalmopatía de Graves/metabolismo , Consumo de Oxígeno/fisiología , Oxígeno/metabolismo , Retina/metabolismo , Vasos Retinianos/diagnóstico por imagen , Adulto , Femenino , Oftalmopatía de Graves/diagnóstico , Humanos , Masculino , Oftalmoscopía , Oximetría , Estudios RetrospectivosRESUMEN
BACKGROUND: Tumors exhibit metabolic heterogeneity, influencing cancer progression. However, understanding metabolic diversity in retinoblastoma (RB), the primary intraocular malignancy in children, remains limited. METHODS: The metabolic landscape of RB was constructed based on single-cell transcriptomic sequencing from 11 RB and 5 retina samples. Various analyses were conducted, including assessing overall metabolic activity, metabolic heterogeneity, and the correlation between hypoxia and metabolic pathways. Additionally, the expression pattern of the monocarboxylate transporter (MCT) family in different cell clusters was examined. Validation assays of MCT1 expression and function in RB cell lines were performed. The therapeutic potential of targeting MCT1 was evaluated using an orthotopic xenograft model. A cohort of 47 RB patients was analyzed to evaluate the relationship between MCT1 expression and tumor invasion. RESULTS: Distinct metabolic patterns in RB cells, notably increased glycolysis, were identified. This metabolic heterogeneity correlated closely with hypoxia. MCT1 emerged as the primary monocarboxylate transporter in RB cells. Disrupting MCT1 altered cell viability and energy metabolism. In vivo studies using the MCT1 inhibitor AZD3965 effectively suppressed RB tumor growth. Additionally, a correlation between MCT1 expression and optic nerve invasion in RB samples suggested prognostic implications. CONCLUSIONS: This study enhances our understanding of RB metabolic characteristics at the single-cell level, highlighting the significance of MCT1 in RB pathogenesis. Targeting MCT1 holds promise as a therapeutic strategy for combating RB, with potential prognostic implications.
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PURPOSE: The purpose of this study was to investigate the fibroblast growth factor receptor 2 (FGFR2) gene in three Chinese patients with Crouzon syndrome and to characterize the related clinical features. METHODS: A single family underwent complete ophthalmic examinations, and three patients were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood collected from members of the family as well as from 100 unrelated control subjects from the same population. Exons 8 and 10 of FGFR 2 were amplified by polymerase chain reaction (PCR) and directly sequenced. We performed ophthalmic examinations, including best-corrected visual acuity, slit-lamp examination, fundus examination, Pentacam, Goldmann perimetry, and computed tomography (CT) of the skull. RESULTS: The three patients were affected with shallow orbits and ocular proptosis, accompanied by mid-face hypoplasia and craniosynostosis, but had clinically normal hands and feet. A heterozygous FGFR2 missense mutation c.1030G>C (Ala344Pro) in exon 10 was identified in the affected individuals, but not in any of the unaffected family members or the normal controls. The mutation we identified has not previously been reported, either in China or abroad. CONCLUSIONS: Although FGFR2 mutations and polymorphisms have been reported in various ethnic groups, especially in the area of osteology, we report, for the first time, the identification of one new FGFR2 gene mutation in Chinese patients with Crouzon syndrome.
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Pueblo Asiatico/genética , Disostosis Craneofacial/genética , Craneosinostosis/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Secuencia de Bases , Estudios de Casos y Controles , Niño , Disostosis Craneofacial/complicaciones , Disostosis Craneofacial/patología , Craneosinostosis/complicaciones , Craneosinostosis/patología , Exones , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación Missense , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , Agudeza Visual , Adulto JovenRESUMEN
PURPOSE: The purposed of this study was to investigate the fibroblast growth factor receptor 2 (FGFR2) gene in one Chinese family with Crouzon syndrome and to characterize the related clinical features. METHODS: One family underwent complete ophthalmic examinations, and two patients were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood collected from the family and 100 unrelated control subjects from the same population. Exons 8 and 10 of FGFR2 were amplified by polymerase chain reaction (PCR) and directly sequenced. We performed ophthalmic examinations, including best-corrected visual acuity, slit-lamp examination, fundus examination, Pentacam, Goldmann perimetry, and computed tomography (CT) of the skull. RESULTS: The two patients were affected with shallow orbits and ocular proptosis, accompanied by midface hypoplasia, craniosynostosis, and clinically normal hands and feet. A heterozygous FGFR2 missense mutation c.866A>C (Gln289Pro) in exon 8 was identified in the affected individuals, but not in any of the unaffected family members and the normal controls. CONCLUSIONS: Although FGFR2 mutations and polymorphisms have been reported in various ethnic groups, especially in the area of osteology, we report, for the first time, the identification of one new FGFR2 mutation in Chinese patients with Crouzon syndrome.
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Disostosis Craneofacial/genética , Mutación Missense , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Adulto , Sustitución de Aminoácidos , Pueblo Asiatico/genética , Secuencia de Bases , Niño , China , Análisis Mutacional de ADN , Cartilla de ADN/genética , Exones , Femenino , Heterocigoto , Humanos , Masculino , LinajeRESUMEN
Importance: Mild thyroid-associated ophthalmopathy (TAO) negatively impacts quality of life, yet no clinical guidelines for its treatment are available. Existing evidence supports the use of doxycycline in treating mild TAO. Objective: To evaluate the short-term (12 weeks) efficacy of doxycycline in treating mild TAO. Design, Setting, and Participants: In this placebo-controlled multicenter randomized double-masked trial, 148 patients were assessed for eligibility. After exclusions (patients who were pregnant or lactating, had an allergy to tetracyclines, or had uncontrolled systematic diseases), 100 patients with mild TAO (orbital soft tissue affected mildly) at 5 centers in China were enrolled from July 2013 to December 2019 and monitored for 12 weeks. Interventions: Participants were randomly assigned 1:1 to receive doxycycline (50 mg) or placebo once daily for 12 weeks. Main Outcomes and Measures: The primary outcome was the rate of improvement at 12 weeks compared with baseline assessed by a composite indicator of eyelid aperture (reduction ≥2 mm), proptosis (reduction ≥2 mm), ocular motility (increase ≥8°), and Graves ophthalmopathy-specific quality-of-life (GO-QOL) scale score (increase ≥6 points). Adverse events were recorded. Results: A total of 50 participants were assigned to doxycycline and 50 to placebo. The mean (SD) age was 36.7 (9.1) years; 75 participants (75.0%) were female and 100 (100.0%) were Asian. Medication compliance was checked during participant interviews and by counting excess tablets. At week 12, the improvement rate was 38.0% (19 of 50) in the doxycycline group and 16.0% (8 of 50) in the placebo group (difference, 22.0%; 95% CI, 5.0-39.0; P = .01) in the intention-to-treat population. The per-protocol sensitivity analysis showed similar results (39.6% [19 of 48] vs 16.0% [8 of 50]; difference, 23.6%; 95% CI, 6.4-40.8; P = .009). No adverse events other than 1 case of mild gastric acid regurgitation was recorded in either group. Conclusions and Relevance: The results of this study indicate that oral doxycycline, 50 mg daily, resulted in greater improvement of TAO-related symptoms at 12 weeks compared with placebo in patients with mild TAO. These findings support the consideration of doxycycline for mild TAO but should be tempered by recognizing the relatively short follow-up and the size of the cohort. Trial Registration: ClinicalTrials.gov Identifier: NCT02203682.
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Doxiciclina , Oftalmopatía de Graves , Humanos , Femenino , Adulto , Masculino , Doxiciclina/efectos adversos , Oftalmopatía de Graves/tratamiento farmacológico , Calidad de Vida , Lactancia , Antibacterianos/efectos adversos , Método Doble CiegoRESUMEN
IL-23/IL-23R and PGE2/EP2+EP4 have been recognized as crucial signals that promote Th17 differentiation in many autoimmune diseases, including thyroid-associated ophthalmopathy (TAO). However, the interactive role of IL-23R in IL-23/Th17 signaling and PGE2/Th17 signaling has not been clarified in TAO. Furthermore, the role of IL-38, a novel anti-inflammatory cytokine, has not been explored in TAO. Thus, we aimed to investigate the roles of IL-23R and IL-38 in the pathogenesis of TAO. Activated peripheral blood mononuclear cells (PBMCs) were cultured with or without IL-23 and PGE2. The results showed that IL-23R and IL-17A were upregulated to different degrees and reached the highest levels with both stimuli, indicating that IL-23 induced PBMCs to secrete PGE2, which further boosted the proportion of IL-23R+CD4+T cells to promote IL-17A secretion. Pretreatment with antagonists aimed at EP2/EP4 receptors diminished PGE2-induced upregulation of IL-23R and IL-17A. IL-38 in TAO patients was increased. Activated orbital fibroblasts (OFs) and PBMCs were pretreated with different concentrations of IL-38. IL-23R and IL-17A expression in circulating PBMCs and IL-6 and IL-8 in resident OFs were suppressed by IL-38 at relatively low concentrations. Our findings suggest that the feedback loop of IL-23/IL-23R/PGE2/EP2+EP4/IL-23R/IL-17A plays a significant role in the pathogenesis of TAO and that IL-23R is one of the key targets. Increased IL-38 in TAO could not only inhibit the expression of IL-23R and IL-17A in PBMCs but also suppress inflammation in OFs. Therapies targeting IL-23R may be effective, and IL-38 could be a potential therapeutic approach for TAO.
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Oftalmopatía de Graves/metabolismo , Interleucina-17/metabolismo , Interleucina-1/metabolismo , Receptores de Interleucina/metabolismo , Células Th17/metabolismo , Adulto , Estudios de Casos y Controles , Células Cultivadas , Dinoprostona/metabolismo , Retroalimentación Fisiológica , Femenino , Fibroblastos/inmunología , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Oftalmopatía de Graves/diagnóstico , Oftalmopatía de Graves/genética , Oftalmopatía de Graves/inmunología , Humanos , Interleucina-1/genética , Interleucina-23/metabolismo , Masculino , Persona de Mediana Edad , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Células Th17/efectos de los fármacos , Células Th17/inmunología , Adulto JovenRESUMEN
Cell cycle deregulation is involved in the pathogenesis of many cancers and is often associated with protein kinase aberrations, including the polo-like kinase 1 (PLK1). We used retinoblastoma, an intraocular malignancy that lacks targeted therapy, as a disease model and set out to reveal targetability of PLK1 with a small molecular inhibitor ON-01910.Na. First, transcriptomic analysis on patient retinoblastoma tissues suggested that cell cycle progression was deregulated and confirmed that PLK1 pathway was upregulated. Next, antitumor activity of ON-01910.Na was investigated in both cellular and animal levels. Cytotoxicity induced by ON-01910.Na was tumor specific and dose dependent in retinoblastoma cells, while nontumor cells were minimally affected. In three-dimensional culture, ON-01910.Na demonstrated efficient drug penetrability with multilayer cell death. Posttreatment transcriptomic findings revealed that cell cycle arrest and MAPK cascade activation were induced following PLK1 inhibition and eventually resulted in apoptotic cell death. In Balb/c nude mice, a safe threshold of 0.8 nmol intravitreal dosage of ON-01910.Na was established for intraocular safety, which was demonstrated by structural integrity and functional preservation. Furthermore, intraocular and subcutaneous xenograft were significantly reduced with ON-01910.Na treatments. For the first time, we demonstrated targetability of PLK1 in retinoblastoma by efficiently causing cell cycle arrest and apoptosis. Our study is supportive that local treatment of ON-01910.Na may be a novel, effective modality benefiting patients with PLK1-aberrant tumors.
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Antineoplásicos/farmacología , Proteínas de Ciclo Celular/metabolismo , Glicina/análogos & derivados , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Sulfonas/farmacología , Animales , Antineoplásicos/efectos adversos , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Perfilación de la Expresión Génica/métodos , Glicina/efectos adversos , Glicina/farmacología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Neoplasias de la Retina/genética , Neoplasias de la Retina/patología , Retinoblastoma/genética , Retinoblastoma/patología , Sulfonas/efectos adversos , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Quinasa Tipo Polo 1RESUMEN
PURPOSE: To investigate the clinical features and treatment outcomes of IgG4-related ophthalmic disease (IgG4-ROD) among idiopathic orbital inflammatory disease (IOID) patients. METHODS: The medical records of 165 biopsy-proven IOID patients were retrospectively reviewed. Biopsy specimens were immunostained to detect IgG4 and IgG, and data regarding the clinicopathologic features, treatment outcomes, and recurrence were analyzed. RESULTS: Among the 165 IOID patients enrolled, 100 (60.6%) were histopathologically IgG4-positive. The IgG4-positive patients had a lower rate of painful swelling or mass (17.0% versus 33.8%, p = 0.013), a longer symptom duration (p = 0.070), and a lower proportion of eyelid hyperemia (39.0% versus 58.5%, p = 0.014) than the IgG4-negative patients. Increased Ki-67 expression (15.02 ± 6.86%, p < 0.001) was observed in the IgG4-positive patients with characteristic pathological manifestations (more lymphocyte infiltration, nodular plasma cell infiltration, and follicular hyperplasia). IgG4-positive group had a higher recurrence rate in the subgroup of patients treated with surgery plus oral glucocorticoids (p = 0.046), and combined radiotherapy group has a higher cumulative proportion with recurrence (p = 0.011). CONCLUSION: Over 60% of biopsy-proven IOID were classified as IgG4-ROD with a stronger proliferation potential. Additional radiotherapy after surgical debulking with oral corticosteroids still has a higher relapse rate, and more effective treatments are needed to prevent recurrence.
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Seudotumor Orbitario , Biopsia , China/epidemiología , Humanos , Inmunoglobulina G , Seudotumor Orbitario/diagnóstico , Seudotumor Orbitario/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
Background: Idiopathic orbital inflammation (IOI) is a disfiguring and vision-threatening fibroinflammatory disorder. The pathogenesis of IOI has not been elucidated. We sought to clarify the regulatory T cell (Treg) distribution and function in patients with IOI. Methods: The frequency, phenotype and function of Tregs were identified by multicolor flow cytometry and in vitro cell functional assays. Plasma and tissue samples were obtained to investigate cytokines, chemokines and their receptors of interest by relative real-time polymerase chain reaction (PCR) and Luminex assays. Results: Compared with healthy subjects, patients with IOI exhibited obvious increases of Tregs in peripheral blood and affected orbital tissues. Circulating Tregs from patients with IOI were significantly more polarized to a Th17-like phenotype with defective regulatory function, whereas orbit-derived Tregs were polarized to a Th2-like phenotype. Furthermore, ST2 expression levels in circulating Tregs and interleukin (IL)-33 mRNA levels in orbital tissues were decreased in IOI. IL-33 restored the suppressive function of Tregs, reduced interferon (IFN)-γ production by Tregs and decreased the activation of orbital fibroblasts (OFs) cocultured with Tregs in IOI. Conclusion: Increased Tregs with proinflammatory and profibrotic polarization were first identified in IOI, suggesting that Treg plasticity and heterogeneity plays an essential role in IOI pathogenesis. Additionally, our study identified a regulatory effect of IL-33 on inflammation and fibrosis in IOI. Reversing the plastic Tregs via IL-33 might be a potential option for IOI patients.
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Plasticidad de la Célula , Inflamación/inmunología , Enfermedades Orbitales/inmunología , Linfocitos T Reguladores/inmunología , Estudios de Casos y Controles , Células Cultivadas , Técnicas de Cocultivo , Fibroblastos/inmunología , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis , Humanos , Inflamación/sangre , Inflamación/diagnóstico , Mediadores de Inflamación/sangre , Interferón gamma/metabolismo , Proteína 1 Similar al Receptor de Interleucina-1/sangre , Interleucina-33/sangre , Interleucina-33/genética , Enfermedades Orbitales/sangre , Enfermedades Orbitales/diagnóstico , Fenotipo , Linfocitos T Reguladores/metabolismoRESUMEN
PURPOSE: To evaluate patient pain and discomfort following oculoplastic surgery performed under general anesthesia and to assess key factors associated with postoperative pain and discomfort. METHODS: A prospective observational cohort study was conducted among 212 consecutive patients who underwent oculoplastic surgery performed under general anesthesia. The patients were assessed according to quantified levels of pain and discomfort postoperatively. Analgesic requests were recorded, and responses were statistically analyzed. RESULTS: Pain and discomfort after oculoplastic surgery under general anesthesia were reported by 32.1% and 28.3% of the patients, respectively; 2.8% of the patients requested analgesic medication within 18 hours after surgery. The patients who underwent orbital decompression, secondary orbital implantation, and orbital fracture repair were more likely to develop significant postoperative pain and discomfort (P<0.001), and the patients who underwent enucleation/evisceration during orbital implantation were more likely to develop postoperative discomfort (P<0.001). The predictors of pain were smoking history, prior surgery on the operative eye, and anxiety (P<0.05), and the predictor of discomfort was anxiety (P<0.05). CONCLUSION: Patients undergoing oculoplastic surgery tend to experience postoperative pain and discomfort. Anxiety is a risk factor for both postoperative pain and discomfort, while smoking history and prior surgery on the operative eye may be associated with postoperative pain.
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The success of rituximab for the treatment of active Graves' orbitopathy (GO) suggests that B cells play a critical role in intraorbital inflammation. B cell activating factor (BAFF) and its homolog a proliferation-inducing ligand (APRIL) are critical for B cell survival. However, the contribution of BAFF/APRIL to GO remains unclear. We sought to determine the role of BAFF/APRIL in the orbits of GO, and found that BAFF was markedly upregulated, while APRIL was not. Additionally, cultured GO orbital fibroblasts (GO-OFs)2 expressing BAFF were induced to produce a large amount of BAFF. In contrast, a weak APRIL expression was detected in the OFs, and they exhibited a slight response to stimulation. Notably, pretreated GO-OFs promoted B cell survival, and this effect was significantly inhibited by a BAFF-R neutralizing antibody. This study indicates that OFs from GO can express BAFF and mediate the intraorbital survival of B cells via BAFF mechanism.
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Factor Activador de Células B/metabolismo , Linfocitos B/patología , Citocinas/farmacología , Fibroblastos/patología , Oftalmopatía de Graves/patología , Órbita/patología , Factor Activador de Células B/genética , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Femenino , Humanos , Mediadores de Inflamación/farmacología , Interferón gamma/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Solubilidad , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The current study was performed with aim to investigate the fibroblast growth factor receptor 2 (FGFR2) gene in two Chinese families with two different forms of syndromic craniosynostosis, and to characterize their associated clinical features. Two families underwent complete ophthalmic examinations, and two patients from each family were diagnosed with craniosynostosis. Genomic DNA was extracted from leukocytes of peripheral blood collected from these two families and from 200 unrelated subjects within the same population as controls. Exons 8 and 10 of the FGFR2 gene were amplified by polymerase chain reaction and directly sequenced. Ophthalmic examinations of the two patients revealed shallow orbits and ocular proptosis, accompanied by midface hypoplasia and craniosynostosis. Case 1 had retinal detachment, abnormal limbs and hands, while case 2 exhibited normal hands and feet upon clinical examination. A heterozygous FGFR2 missense mutation c.833G>T (C278F) in exon 8 was identified in these two patients, but not in unaffected family members or the normal controls. Although FGFR2 gene mutations and polymorphisms have been studied in various ethnic groups, we report a mutation of FGFR2 in two different Chinese patients with two different types of syndromic craniosynostosis.
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Alelos , Sustitución de Aminoácidos , Craneosinostosis/diagnóstico , Craneosinostosis/genética , Estudios de Asociación Genética , Mutación , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Niño , Codón , Análisis Mutacional de ADN , Exones , Facies , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Radiografía , Síndrome , Tomografía Computarizada por Rayos XRESUMEN
The aim of the present study was to identify mutations in the fibroblast growth factor receptor 2 (FGFR2) gene in patients with Crouzon syndrome and characterize the associated clinical features. A total of two Chinese patients diagnosed with Crouzon syndrome underwent complete examinations, including bestcorrected visual acuity, slitlamp, examination, fundus examination, optical coherence tomography and computed tomography of the skull. Genomic DNA was extracted from peripheral blood samples collected from the patients, as well as their family members and 200 unrelated control subjects from the same population. Exons 8 and 10 in the FGFR2 gene were amplified by polymerase chain reaction and directly sequenced. Patient #1 had a heterozygous missense mutation (c.1025G>A, p.C342Y) in exon 10 of FGFR2. Patient #2 had a heterozygous mutation (c.1084+1 G>T; IVS10+1G>T) in intron 10. The mutations were not present in any of the unaffected family members or unrelated control subjects. These findings expand the mutation spectrum of FGFR2, and are valuable for genetic counseling in addition to prenatal diagnosis in patients with Crouzon syndrome.
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Disostosis Craneofacial/genética , Predisposición Genética a la Enfermedad , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Adulto , Pueblo Asiatico , Preescolar , Disostosis Craneofacial/patología , Exones/genética , Femenino , Heterocigoto , Humanos , Mutación/genética , LinajeRESUMEN
OBJECTIVE: To study the clinical features, preoperative diagnosis and surgical choice of orbital cavernous hemangioma. METHODS: Records of all cavernous hemangioma patients (209 cases) who were seen in Eye Hospital, Zhongshan Ophthalmic Center, Sun Yat-sen University from January 1, 1986 to December 31, 2000 were reviewed. RESULTS: Among 209 cases, 123 patients were females and 86 were males. The left orbit was affected in 123 cases and the right orbit in 86 cases. No case was bilaterally involved. The mean age was 39.2 years old, ranging from 5 to 68 years. A painless, gradually progressive proptosis and visual disturbance were the main clinical signs. Ninety-five percent (199/209) of them could be accurately diagnosed preoperatively based on ultrasound scan and CT/MRI examination. The tumors were removed successfully by the surgical procedure of standard lateral orbitotomy in 36% (75/209) of patients and anterior orbitotomy in 64% cases (134/209). CONCLUSIONS: Nearly all patients with cavernous hemangioma could be correctly diagnosed by preoperative image studying. The simple surgical procedure of anterior orbitotomy can be successfully used in about two third of cases with less surgical complication.
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Hemangioma Cavernoso/diagnóstico , Hemangioma Cavernoso/cirugía , Neoplasias Orbitales/diagnóstico , Neoplasias Orbitales/cirugía , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , UltrasonografíaRESUMEN
PURPOSE: To compare the clinical effects of different cycles of carboplatin, etoposide, and vincristine (CEV) regimens of adjuvant chemotherapy in postenucleation high-risk patients with IRSS Stage I retinoblastoma (RB). METHODS: A retrospective analysis of 53 RB patients hospitalized in the Zhongshan Ophthalmic Center of Sun Yat-sen University was performed. All patients had unilateral involvement, received enucleation treatment, were diagnosed as RB by pathology, and had high-risk pathological factors. Patients either refused postoperative chemotherapy or received three or six cycles of CEV regimen chemotherapy. The clinical information, treatment, and results of patients in all groups were compared. RESULTS: A total of 19 cases refused postenucleation chemotherapy, 18 cases received three cycles, and 16 cases received six cycles of the CEV regimen chemotherapy. The 5-year disease-free survival rate and the overall survival (OS) rate in the chemotherapy group were higher than those in the non-chemotherapy group (97.1% vs. 63.2%, p = 0.001) and were not different between the three-cycle chemotherapy group and the six-cycle chemotherapy group (94.4% vs. 100%, p = 0.35). CONCLUSION: After eye enucleation for patients with high-risk unilateral RB, the CEV regimen chemotherapy was associated with a higher survival rate. The three-cycle CEV regimen adjuvant chemotherapy was effective and is expected to replace the six-cycle CEV regimen chemotherapy.
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Carboplatino/administración & dosificación , Etopósido/administración & dosificación , Enucleación del Ojo , Cuidados Posoperatorios/métodos , Neoplasias de la Retina/terapia , Retinoblastoma/terapia , Vincristina/administración & dosificación , Antineoplásicos/administración & dosificación , Preescolar , China/epidemiología , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Estadificación de Neoplasias , Neoplasias de la Retina/diagnóstico , Neoplasias de la Retina/mortalidad , Retinoblastoma/diagnóstico , Retinoblastoma/mortalidad , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Factores de Tiempo , Resultado del TratamientoRESUMEN
Crouzon syndrome, a dominantly inherited disorder and the most common type of craniosynostosis syndrome, is caused by mutations in the fibroblast growth factor receptor 2 (FGFR 2) gene, and characterized by craniosynostosis, shallow orbits, ocular proptosis, midface hypoplasia and a curved, beaklike nose. The purpose of the present study was to investigate the fibroblast growth factor receptor 2 (FGFR 2) gene in two Chinese families with Crouzon syndrome and to characterize the associated clinical features. Two families underwent complete ophthalmic examination, and three patients in two families were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood samples, which were collected from the family members and 200 unrelated control subjects from the same population. Exons 8 and 10 of the FGFR 2 gene were amplified using polymerase chain reaction analysis and were directly sequenced. Ophthalmic examinations, including bestcorrected visual acuity, slitlamp examination, fundus examination and Computerized Tomography scans, and physical examinations were performed to exclude systemic diseases. These patients were affected with shallow orbits and ocular proptosis, accompanied by midface hypoplasia, craniosynostosis, strabismus or papilloedema, with clinically normal hands and feet. A heterozygous FGFR 2 missense mutation, c.811812insGAG (p.273insGlu) in exon 8 was identified in the affected individual, but not in the unaffected family members or the normal control individuals in family 1. In family 2, another heterozygous FGFR 2 missense mutation, c.842A>G (P.Tyr281Cys or Y281C), in exon 8 was identified in the affected boy and his mother, but not in the unaffected family members or the normal control individuals. Although FGFR 2 gene mutations and polymorphisms have been reported in various ethnic groups, particularly in the area of osteology, the present study reported for the first time, to the best of our knowledge, the identification of two novel FGFR 2 gene mutations in Chinese patients with Crouzon syndrome.
Asunto(s)
Disostosis Craneofacial/metabolismo , Heterocigoto , Mutación Missense , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Pueblo Asiatico/genética , Preescolar , Disostosis Craneofacial/genética , Análisis Mutacional de ADN , Femenino , Humanos , Lactante , Masculino , LinajeRESUMEN
Aim. To study the efficacy and safety of subantimicrobial dose (SD) doxycycline(50 mg/d) in patients with active and moderate-to-severe Graves' orbitopathy (GO). Methods. Thirteen patients with active and moderate-to-severe GO received once daily oral doxycycline (50 mg/d) for 12 wk. Treatment response at 24 wk was used as the primary outcome, measured by a composite of improvement in Clinical Activity Score (CAS), diplopia, motility, soft tissue swelling, proptosis, and eyelid aperture. Secondary outcome was the change of quality of life score (QoL, including visual functioning subscale and appearance subscale). Adverse events were also recorded. Results. Overall improvement was noted in eight out of 13 patients (61.5%, 95% CI 31.6%-86.1%). Both CAS and soft tissue swelling significantly ameliorated in eight patients at 24 wk. Five patients (38.5%) had improvement in ocular motility of ≥8 degrees. Eyelid aperture (46.2%) also decreased remarkably. For QoL, a significant improvement in appearance subscale (P = 0.008) was noted during the study, whereas no difference was observed in visual functioning subscale (P = 0.21). Two patients reported mild stomachache at 12 wk. Conclusions. SD doxycycline appears to be effective and safe for the treatment of active and moderate-to-severe GO. It might serve as a new promising therapeutic strategy for GO. This trial is registered with NCT01727973.
RESUMEN
Single nucleotide polymorphisms (SNPs) of p53 rs1042522, MDM2 rs2279744 and p21 rs1801270, all in the p53 pathway, which plays a crucial role in DNA damage and genomic instability, were reported to be associated with cancer risk and pathologic characteristics. This case-control study was designed to analyse the association between these SNPs and retinoblastoma (RB) in a Chinese Han population. These SNPs in 168 RB patients and 185 adult controls were genotyped using genomic DNA from venous blood. No significant difference was observed in allele or genotypic frequencies of these SNPs between Chinese RB patients and controls (all P > 0.05). However, the rs1042522 GC genotype showed a protective effect against RB invasion, as demonstrated by event-free survival (HR = 0.53, P = 0.007 for GC versus GG/CC). This effect was significant for patients with a lag time >1 month and no pre-enucleation treatment (P = 0.007 and P = 0.010, respectively), indicating an interaction between p53 rs1042522 and clinical characteristics, including lag time and pre-enucleation treatment status. Thus, the rs1042522 SNP may be associated with RB invasion in the Han Chinese population; however, further large and functional studies are needed to assess the validity of this association.
Asunto(s)
Pueblo Asiatico/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Retinoblastoma/genética , Proteína p53 Supresora de Tumor/genética , Adulto , China , Femenino , Frecuencia de los Genes/genética , Humanos , Estimación de Kaplan-Meier , Masculino , Modelos de Riesgos Proporcionales , Factores de RiesgoRESUMEN
OBJECTIVE: To study the pathological features of uveal melanoma and to evaluate their influence on patients' prognosis. METHODS: Paraffin embedded uveal melanoma tissues of 115 cases were examined using routine pathologic methods. Three histological types were classified according to the modified Callender system and patients were followed clinically. The data were done regression and survival analysis by SPSS statistic soft. RESULTS: The patient with epithelial cell type, mixed type, and spindle cell type uveal melanoma have different life times, the average life time is 35.6 +/- 21.5 months, 63.7 +/- 37.0 months, 69.5 +/- 36.5 months in turn, patients with epithelial uveal melanoma had shorter survival time than other two types. The survival time was negatively related to the largest diameter of contact area with the sclera, the largest height and the depth of tumor invasion to the sclera. CONCLUSIONS: Epithelial uveal melanoma is more malignant than the other two types. Histological classification of this tumor combined with other pathologic features can indicate the patient's prognosis.